Worldwide, 400 million people acquire malaria each year, contributing to significant political, social and economic instability in the developing countries. Malaria infection leads to production of high levels of pyrogenic cytokines, such as TNFa and IFN?, which orchestrate the host response to infection as well as cause the symptoms observed during disease. Our studies suggest that the Myeloid Differentiation Factor 88 (MyD88), an adaptor-signaling molecule for the IL-1 receptor (and the related IL-18r and IL-33r) as well as Toll- like receptors (TLRs), is critical for initiation of this early inflammatory response and pathogenesis of rodent malaria. Our microarray analysis of peripheral blood mononuclear cells from patients with acute malaria demonstrate enhanced expression of genes encoding proteins that are critical in the TLR signaling pathway. We hypothesize that upon overwhelming malaria infection, innate immune receptors in phagocytes are responsible for the intense cytokinemia and subsequent morbidity and death. This hypothesis, of course, is neither innovative nor risky. But the most basic details of malaria-related cytokinemia are yet to be worked out. While the paucity of published data concerning monocytes and dendritic cells is surprising, the role of polymorphonuclear leukocytes (PMN) as a source of cytokines and other mediators has been entirely overlooked. PMNs are the most abundant leukocytes and produce many mediators of inflammation. Furthermore, PMNs express TLR2, TLR4, and TLR9 that are critical for the innate immune response to Plasmodium glycolipids and DNA. We hypothesize that PMNs play an important role in the innate immune response during human acute malaria episodes and hence are potential targets for novel immune therapies. Thus, we intend to evaluate: (i) the ability of PMNs in comparison to other phagocytes obtained from healthy and malaria patients to respond in vitro to immunostimulatory malaria components;and (ii) ex vivo cytokine production and gene expression in PMNs, obtained from malaria patients before and after parasitological cure by chemotherapy. Ultimately, we hope to define the contribution of innate immune receptors in neutrophil responses and systemic inflammation during acute infection with P. falciparum. Such knowledge may contribute to new therapeutic insights to the treatment of malaria. PUBLIC HEALTH RELEVANCE: Malaria is the world's most common infectious disease, and kills millions of individuals annually. US citizens risk obtaining malaria when they travel or are engaged in military operations in tropical areas. The purpose of this grant is to gain a better understanding of why malaria causes disease in the hopes that better therapies can be devised, including an effective vaccine that might prevent malaria.